Hepatitis C-associated osteosclerosis (HCAO) is a rare syndrome characterized by a marked increase in skeletal mass in adults who are infected with the hepatitis C virus. Beyer et al., J. Bone Min. Res., 5:1257-1263 (1990); and Diamond et al., Bone, 19:679-683 (1996). Spine and hip bone mineral densities are elevated as much as two-fold in these affected individuals, who represent the most dramatic example of acquired osteosclerosis in humans. Radiographs show dense bones in the appendicular and axial skeleton, with sparing of the calvarium and facial bones. Biochemical markers of bone formation are usually elevated, and transiliac bone biopsies generally show increased bone formation rates. Nevertheless, osseous tissue from these patients appears histologically to be of good quality with intact lamellar patterns, unlike the abnormal, rapidly remodeling woven bone found in patients with Paget""s bone disease.
To date, ten cases of HCAO have been reported. It is apparent, however, that only a small percentage of all patients infected with hepatitis C develop osteosclerosis, since skeletal radiographs of 107 randomly selected hepatitis C infected patients failed to show dense bones. Beyer et al., Am. J. Med., 95:660-662 (1990). Thus, although it is uncertain whether hepatitis C is the causative agent of the skeletal disease, a plausible hypothesis is that either hepatitis C or another parenterally transmitted agent increases hepatic production of a growth factor(s) that stimulate osteoblast function.
The invention is based on the discovery that insulin-like growth factor binding protein 2 (IGFBP2) facilitates targeting of insulin-like growth factors (IGFs), and in particular, IGFIIE, to skeletal tissue. Complexes of IGFIIE polypeptide and IGFBP2 polypeptide are effective in stimulating human osteoblast proliferation and can be used for increasing bone mass in patients with osteoporosis.
The invention features a substantially pure complex including an IGFIIE polypeptide and an IGFBP2 polypeptide. IGFIIE polypeptide and IGFBP2 polypeptide can be present in approximately equimolar amounts. The IGFIIE polypeptide can be full-length IGFIIE or a fragment of IGFIIE (e.g. IGFIIE1-87 or IGFIIE1-104). Fragments of IGFIIE have the biological activity of full-length IGFIIE. In particular, a fragment of IGFIIE can be used, as described above.
The invention also features a method of treating an osteoporosis patient. The method includes administering an amount of a complex including an IGFII polypeptide and an IGFBP2 polypeptide effective to increase bone mass in the patient. IGFBP2 polypeptide can be full-length IGFBP2. IGFII polypeptide can be IGFII or IGFIIE.
The invention also relates to a method of targeting a compound to skeletal extracellular matrix of a patient. The method includes administering a complex to the patient. The complex includes an IGFIIE polypeptide, an IGFBP2 polypeptide and the compound. The IGFBP2 polypeptide can be full-length IGFBP2. The compound includes a chemotherapeutic agent or a growth factor such as an IGFII polypeptide or IGFI. Full-length IGFIIE and fragments thereof that have the biological activity of full-length IGFIIE are particularly useful IGFII polypeptides.
The invention also features a pharmaceutical composition including a complex including IGFII polypeptide and IGFBP2 polypeptide in an amount effective to increase bone mass in a mammal and a pharmaceutically acceptable carrier.
The invention also features an article of manufacturing including packaging material and a pharmaceutical agent contained within the packaging material. The pharmaceutical agent includes a complex including an IGFII polypeptide and an IGFBP2 polypeptide and is therapeutically effective for increasing bone mass. The packaging material includes a label or package insert indicating that the pharmaceutical agent can be used for increasing bone mass or treating osteoporosis.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.